The goal of the proposed research is to examine the STAT signaling events following exposure of CLL cells to bryostatin. Previous studies have demonstrated that STATs are key mediators of intracellular stimuli in lymphocytes. and that STATs are targeted by chemotherapeutic agents used to treat CLL. Preliminary studies have indicated that STATs are activated in CLL cells induced to differentiate by bryostatin. To examine the possibility that STAT signal transduction is important for bryostatin induced differentiation of CLL cells. the mechanism by which bryostatin leads to STAT activation will be examined. The role of STAT-dependent gene activation in CLL cells induced to differentiate by bryostatin also will be examined. Direct evidence for the participation of STATs in differentiation will be assayed by expressing dominant negative forms of STATs in CLL cells. Bryostatin is known to be both an agonist and an antagonist of the PKC pathway. therefore. the relationship between the STAT signal transduction pathway and the PKC pathway will be defined. Findings will be related to clinical studies by examining the effects of the combination of bryostatin and fludarabine on STAT signal transduction and CLL cell death. Information derived from these studies will indicate the importance of a novel, non-PKC signaling pathway stimulated by bryostatin and will provide a better understanding of the intracellular signaling events underlying the biological effects of bryostatin. particularly when combined with other antileukemia drugs.